Complement Activation- Classical, Alternative and Lectin Pathways


The complement system is a part of the immune system that helps defend against infection by enhancing the ability of antibodies and phagocytic cells to clear microbes and damaged cells, promoting inflammation, and attacking the pathogen`s cell membrane. The complement system consists of a number of small proteins that circulate in the blood as inactive precursors or reside on cell surfaces. When stimulated by one of several triggers, these proteins undergo a series of proteolytic reactions that result in the generation of biologically active products.

There are three main pathways of complement activation: the classical pathway, the alternative pathway, and the lectin pathway. These pathways differ in how they are initiated, but they converge into a common terminal pathway that leads to the formation of the membrane attack complex (MAC), a pore-like structure that lyses target cells.

  • The classical pathway is activated by certain isotypes of antibodies (mainly IgM and IgG) bound to antigens on the surface of microbes or other structures. This pathway involves a plasma protein called C1q that recognizes and binds to the Fc portion of the antibodies, activating two associated serine proteases, C1r and C1s, that initiate a cascade of enzyme activation involving other complement proteins. The classical pathway is one of the major effector mechanisms of the humoral arm of adaptive immune responses.
  • The alternative pathway is activated by microbial cell surfaces or certain immunoglobulins in the absence of antibody. This pathway involves a complement protein called C3 that directly recognizes and binds to certain microbial structures, such as lipopolysaccharide (LPS) on gram-negative bacteria. C3 is also constantly activated in solution at a low level and binds to cell surfaces, but it is inhibited by regulatory molecules present on mammalian cells. Because microbes lack these regulatory molecules, the spontaneous activation can be amplified on microbial surfaces. Thus, this pathway can distinguish normal self from foreign microbes on the basis of the presence or absence of the regulatory proteins. The alternative pathway is phylogenetically older than the classical pathway and represents an innate defense mechanism against infection.
  • The lectin pathway is activated by a plasma protein called mannose-binding lectin (MBL) that recognizes and binds to mannose, fucose, or N-acetylglucosamine residues on microbial glycoproteins and glycolipids. MBL is a member of the collectin family with a hexameric structure similar to C1q. After MBL binds to microbes, two zymogens called MASP1 and MASP2 (MBL-associated serine proteases) associate with MBL and initiate downstream proteolytic steps identical to the classical pathway. The lectin pathway resembles the classical pathway structurally and functionally, but it does not require antibody for activation.

All three pathways result in the generation of enzyme complexes that cleave C3 into C3a and C3b, which are biologically active fragments. C3b becomes covalently attached to microbial surfaces or to antibody-antigen complexes, enhancing their phagocytosis by cells that express receptors for C3b. C3a is an anaphylatoxin that stimulates inflammation by inducing mast cell degranulation and chemotaxis of leukocytes. The cleavage of C3 also leads to the formation of C5 convertase, which cleaves C5 into C5a and C5b. C5a is another anaphylatoxin with similar functions as C3a, while C5b initiates the assembly of MAC on target cell membranes. MAC causes osmotic lysis of foreign cells by creating pores in their membranes.

The complement system is regulated by various factors that prevent excessive activation and damage to host cells. These factors include inhibitors of enzyme activity (such as C1 inhibitor), cofactors for factor I-mediated cleavage of C3b and C4b (such as membrane cofactor protein), decay-accelerating factors that dissociate C3 convertase (such as CD55), and membrane-protective proteins that prevent MAC formation (such as CD59). Deficiencies or dysfunctions of these regulatory factors can result in various diseases involving complement-mediated tissue damage or susceptibility to infection.

The complement system represents the dynamic interplay among different pathways, control processes, and other protein systems and cells in the local environment. Complement activation plays an important role in both innate and adaptive immunity by augmenting antibody responses and immunologic memory, lysing foreign cells, clearing immune complexes and apoptotic cells, stimulating inflammation, and modulating other immune functions.